EP0734723A1 - Therapeutic composition for hyperparathyroidism of patient subjected to artificial dialysis - Google Patents

Therapeutic composition for hyperparathyroidism of patient subjected to artificial dialysis Download PDF

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Publication number
EP0734723A1
EP0734723A1 EP94929663A EP94929663A EP0734723A1 EP 0734723 A1 EP0734723 A1 EP 0734723A1 EP 94929663 A EP94929663 A EP 94929663A EP 94929663 A EP94929663 A EP 94929663A EP 0734723 A1 EP0734723 A1 EP 0734723A1
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EP
European Patent Office
Prior art keywords
hyperparathyroidism
linolenic acid
patients
artificial dialysis
therapeutic composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94929663A
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German (de)
French (fr)
Other versions
EP0734723A4 (en
Inventor
Fumikazu Kawagishi
Keiko Yamada
Hiroshi Iguchi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kowa Tekuno Sachi Co Ltd
Idemitsu Materials Co Ltd
Original Assignee
Idemitsu Materials Co Ltd
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Publication of EP0734723A1 publication Critical patent/EP0734723A1/en
Publication of EP0734723A4 publication Critical patent/EP0734723A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

  • the present invention relates to a therapeutic composition for hyperparathyroidism of patients subjected to artificial dialysis for suppressing hypersecretion of parathyroid hormone due to hyperparathyroidism.
  • Chronic renal failure exhibits the decrease in the number of nephrons irrespective of the type of the renal disorder.
  • the promoted decrease in the number of nephrons results in the death of the renal function, which requires artificial dialysis.
  • the renal depression due to the decrease in the number of nephrons causes the decrease in serum Ca, the decrease in the production of active vitamin D, the elevation of the serumal Ca set point at which the secretion of parathyroid hormone (hereinafter referred to as PTH) is set to be suppressed, the decrease in the number of parathyroid-activated vitamin D receptors, the metabolic disorder for phosphorus, etc., which cause hypersecretion of PTH that may be followed by secondary hyperparathyroidism.
  • PTH parathyroid hormone
  • PTH is indispensable for the regulation of metabolism of calcium and phosphorus, while having a great influence on the stable maintenance of bone. Hypersecretion of PTH acts on bone, thereby causing fibrous osteitis. It is said that PTH is one of uremic substances which cause anemia, organic ulcer, central nervous neuropathy, itching, hyperlipemia, etc. and it is a significant factor in the presentation of the symptoms of renal osteodystrophy which is a severe complication for patients subjected to artificial dialysis. Many patients who have once suffered from the disorder of renal osteodystrophy are difficult to cure, and the disorder noticeably lowers with the QOL of patients subjected to artificial dialysis.
  • activated vitamin D preparations are administrated to patients with hypocalcemia or those with insufficiency of vitamin D production.
  • preparations involve harmful side effects in that they often cause hypercalcemia and ectopic calcification.
  • Pulse therapy may be administrated to patients resistant to activated vitamin D preparations, which, however, is problematic in that it may cause hypometabolic turnover osteitis, etc., in addition to the above-mentioned disadvantages.
  • activated vitamin D preparations and calcium preparations may be employed, which, however, are still problematic in the same points as above.
  • aluminum hydroxide is a chemical that should not be administered to patients with hyperphosphatemia to be caused by the metabolic disorder of phosphorus, who are subjected to artificial dialysis. Therefore, in place of this, calcium carbonate or calcium acetate preparations are administered to them.
  • calcium preparations must be administered in large quantities with a high risk of hypercalcemia.
  • Low-protein dietary cure may also be employed with the limitation of phosphorus. However, low-protein diets often bring about negative results of trophopathy and hypercatabolism. Surgical treatment of enucleating parathyroid gland may be employed, which, however, brings about serious mental and physical strains of patients.
  • the conventional therapeutical means for hyperparathyroidism are all problematic.
  • the combinations of such means could produce no satisfactory therapeutic effects at present.
  • the present invention has been attained from the above-mentioned viewpoints, and its object is to provide a therapeutic composition for the hyperparathyroidism of patients subjected to artificial dialysis, which exhibits a sufficient curative effect without having any negative influence such as harmful side effects and can produce good results for QOL.
  • the present inventors have assiduously studied in order to attain the above-mentioned object and, as a result, have found that ⁇ -6 unsaturated fatty acids can significantly depress the hypersecretion of PTH to be caused by the hyperparathyroidism of patients subjected to artificial dialysis. On the basis of this finding, we have achieved the present invention.
  • the present invention provides a therapeutic composition for hyperparathyroidism of a patient subjected to artificial dialysis, comprising one or more selected from ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid and derivatives thereof.
  • ⁇ -6 unsaturated fatty acids such as ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid, etc. which are used in the present invention are known as indispensable fatty acids, and it is known that these and their derivatives (hereinafter referred to as " ⁇ -linolenic acid, etc.") have various physiological activities. However, it is unknown at all that these are effective on hyperparathyroidism of patients subjected to artificial dialysis, which we have found for the first time.
  • ⁇ -linolenic acid, etc. to be used in the present invention are fatty acids indispensable to human bodies, and these are safe to patients with a dietary cure such as those subjected to artificial dialysis and can administrated to them without anxiety.
  • the ⁇ -linolenic acid, etc. can be obtained from oils and fats which originates from mold of the genera Mucor, Mortierella, Rizopus, etc., plants such as evening primrose, borage, etc. and also algae such as Spirulina, etc. Extracts from these may be used directly or after having been purified.
  • ⁇ -linolenic acid, etc. can also be obtained by chemical synthesis, and commercially-available products can also be used.
  • Derivatives of the above-mentioned ⁇ -linolenic acid and dihomo- ⁇ -linolenic acid include esters to be obtained by reacting the acids with various alcohols, such as methyl esters, glycerol esters, phospholipids, etc. and also salts to be obtained by reacting the acids with inorganic or organic bases at equivalent molar ratios, such as sodium salts, potassium salts, etc.
  • the form of the therapeutic composition of the present invention for hyperparathyroidism of patients subjected to artificial dialysis is not specifically defined.
  • one or more of the above-mentioned ⁇ -linolenic acid, etc. may be formulated with a binder such as gelatin, etc., a vehicle such as crystalline cellulose, etc., an excipient such as potato starch, sodium alginate, etc., a sweetener such as lactose, sucrose, etc., into powders, tablets, pills or granules.
  • a binder such as gelatin, etc.
  • a vehicle such as crystalline cellulose, etc.
  • an excipient such as potato starch, sodium alginate, etc.
  • a sweetener such as lactose, sucrose, etc.
  • a mixture of ⁇ -linolenic acid, etc. and other oils and fats is encapsulated into soft gelatin capsules, hard gelatin capsules, etc., in accordance with known methods.
  • cyclodextrin clathrates comprising cyclodextrin and ⁇ -linolenic acid, etc. can also be prepared by known methods.
  • vaseline, paraffin, oils and fats, lanolin, etc. are usable as the base.
  • ⁇ -linolenic acid, etc. can be combined with ⁇ -3 unsaturated fatty acids such as ⁇ -linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, etc., ⁇ -5 unsaturated fatty acids such as myristoleic acid, etc., ⁇ -7 unsaturated fatty acids such as palmitoleic acid, etc., ⁇ -9 unsaturated fatty acids such as oleic acid, ercylic acid, etc.; and saturated fatty acids such as lauric acid, myristic acid, etc., at any desired proportions.
  • antioxidants such as vitamin E, ascorbyl palmitate, ascorbyl stearate, etc. may be added thereto.
  • the dose of ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid or its derivative is not specifically defined. However, if too much of it is administered, the patient is apt to have loose bowels.
  • the dose shall be suitably determined, depending on the age, the medical history and the condition of the patient as well as the type of the disorder, etc.
  • the active ingredient may be administrated thereto in an amount of from 50 to 600 mg/day, preferably from 100 to 450 mg/day.
  • the oil or fat containing ⁇ -linolenic acid used herein was extracted according to the method described in Japanese Patent Application Laid-Open No. 63-283589 (1988). Briefly, cultured cells of Mucor circinelloides HUT 1121 (FERM P-9359) was subjected to n-hexane extraction to obtain oil or fat containing ⁇ -linolenic acid.
  • the capsules prepared in the above-mentioned Production Example were administered to four patients subjected to artificial dialysis, who suffer from hyperparathyroidism and have the medical history of hemodialytic treatment shown in Table 1 below, at 7 capsules/day (4 capsules after breakfast and 3 capsules after evening meal a day) which corresponds to 350 mg/day in terms of ⁇ -linolenic acid.
  • the administration was started on the same day for the four patients.
  • the patients Nos. 1 to 3 the administration was continued for 3 months.
  • their data were measured with Allegro Intact PTH kit (produced by Nippon Mediphysics Co.) and are shown in Table 2.
  • Allegro Intact PTH kit produced by Nippon Mediphysics Co.
  • the therapeutic composition of the present invention for hyperparathyroidism of patients who are subjected to artificial dialysis exhibits a sufficient suppressive effect for the hypersecretion of PTH to be caused by hyperparathyroidism and is excellent in safety.

Abstract

A therapeutic composition having a sufficient curative effect on the hyperparathyroidism of a patient subjected to artificial dialysis and a high safety, which contains at least one member selected from among γ-linolenic acid, dihomo-γ-linolenic acid and derivatives thereof as the active ingredient.

Description

    TECHNICAL FIELD
  • The present invention relates to a therapeutic composition for hyperparathyroidism of patients subjected to artificial dialysis for suppressing hypersecretion of parathyroid hormone due to hyperparathyroidism.
    • BACKGROUND ART
  • The recent development of hemodialytic therapy has now much reduced chronic renal failure to be the direct cause of death. The selection of suitable therapy for the disorder has made it possible to live for a long period of time of 20 years or longer. Accordingly, it has become extremely important to improve the quality of life (hereinafter referred to as QOL) of patients (that is, to let patients live an ordinary life without being physically handicapped while ensuring their mental life and without being isolated from social life while ensuring all their positive stability). At present, therefore, the measures against the complications of the disorder from which the patients may suffer while living for a long period of time and also suitable therapeutical means for ensuring the patients' early rehabilitation in society are desired to be established.
  • Chronic renal failure exhibits the decrease in the number of nephrons irrespective of the type of the renal disorder. The promoted decrease in the number of nephrons results in the death of the renal function, which requires artificial dialysis. The renal depression due to the decrease in the number of nephrons causes the decrease in serum Ca, the decrease in the production of active vitamin D, the elevation of the serumal Ca set point at which the secretion of parathyroid hormone (hereinafter referred to as PTH) is set to be suppressed, the decrease in the number of parathyroid-activated vitamin D receptors, the metabolic disorder for phosphorus, etc., which cause hypersecretion of PTH that may be followed by secondary hyperparathyroidism.
  • PTH is indispensable for the regulation of metabolism of calcium and phosphorus, while having a great influence on the stable maintenance of bone. Hypersecretion of PTH acts on bone, thereby causing fibrous osteitis. It is said that PTH is one of uremic substances which cause anemia, organic ulcer, central nervous neuropathy, itching, hyperlipemia, etc. and it is a significant factor in the presentation of the symptoms of renal osteodystrophy which is a severe complication for patients subjected to artificial dialysis. Many patients who have once suffered from the disorder of renal osteodystrophy are difficult to cure, and the disorder noticeably lowers with the QOL of patients subjected to artificial dialysis.
  • It is said that most patients with light renal failure suffer from secondary hyperparathyroidism. The frequency and the degree of the complication increase in the patients who are subjected to artificial dialysis for a long period of time. Therefore, it is necessary to prevent the complication in the early stage of renal failure.
  • To cure secondary hyperparathyroidism, for example, activated vitamin D preparations are administrated to patients with hypocalcemia or those with insufficiency of vitamin D production. However, such preparations involve harmful side effects in that they often cause hypercalcemia and ectopic calcification. Pulse therapy may be administrated to patients resistant to activated vitamin D preparations, which, however, is problematic in that it may cause hypometabolic turnover osteitis, etc., in addition to the above-mentioned disadvantages. In order to lower the serumal Ca set point at which the secretion of PTH is set to be suppressed, activated vitamin D preparations and calcium preparations may be employed, which, however, are still problematic in the same points as above. On the other hand, aluminum hydroxide is a chemical that should not be administered to patients with hyperphosphatemia to be caused by the metabolic disorder of phosphorus, who are subjected to artificial dialysis. Therefore, in place of this, calcium carbonate or calcium acetate preparations are administered to them. However, as having poor phosphorus adsorbability, calcium preparations must be administered in large quantities with a high risk of hypercalcemia. Low-protein dietary cure may also be employed with the limitation of phosphorus. However, low-protein diets often bring about negative results of trophopathy and hypercatabolism. Surgical treatment of enucleating parathyroid gland may be employed, which, however, brings about serious mental and physical strains of patients.
  • As mentioned hereinabove, the conventional therapeutical means for hyperparathyroidism are all problematic. In particular, for patients subjected to artificial dialysis for a long period of time, even the combinations of such means could produce no satisfactory therapeutic effects at present.
    • DISCLOSURE OF THE INVENTION
  • The present invention has been attained from the above-mentioned viewpoints, and its object is to provide a therapeutic composition for the hyperparathyroidism of patients subjected to artificial dialysis, which exhibits a sufficient curative effect without having any negative influence such as harmful side effects and can produce good results for QOL.
  • The present inventors have assiduously studied in order to attain the above-mentioned object and, as a result, have found that ω-6 unsaturated fatty acids can significantly depress the hypersecretion of PTH to be caused by the hyperparathyroidism of patients subjected to artificial dialysis. On the basis of this finding, we have achieved the present invention.
  • The present invention provides a therapeutic composition for hyperparathyroidism of a patient subjected to artificial dialysis, comprising one or more selected from γ-linolenic acid, dihomo-γ-linolenic acid and derivatives thereof.
  • The present invention is described in detail hereinunder.
  • ω-6 unsaturated fatty acids such as γ-linolenic acid, dihomo-γ-linolenic acid, etc. which are used in the present invention are known as indispensable fatty acids, and it is known that these and their derivatives (hereinafter referred to as "γ-linolenic acid, etc.") have various physiological activities. However, it is unknown at all that these are effective on hyperparathyroidism of patients subjected to artificial dialysis, which we have found for the first time.
  • γ-linolenic acid, etc. to be used in the present invention are fatty acids indispensable to human bodies, and these are safe to patients with a dietary cure such as those subjected to artificial dialysis and can administrated to them without anxiety.
  • The γ-linolenic acid, etc. can be obtained from oils and fats which originates from mold of the genera Mucor, Mortierella, Rizopus, etc., plants such as evening primrose, borage, etc. and also algae such as Spirulina, etc. Extracts from these may be used directly or after having been purified. In addition, γ-linolenic acid, etc. can also be obtained by chemical synthesis, and commercially-available products can also be used.
  • Derivatives of the above-mentioned γ-linolenic acid and dihomo-γ-linolenic acid include esters to be obtained by reacting the acids with various alcohols, such as methyl esters, glycerol esters, phospholipids, etc. and also salts to be obtained by reacting the acids with inorganic or organic bases at equivalent molar ratios, such as sodium salts, potassium salts, etc.
  • The form of the therapeutic composition of the present invention for hyperparathyroidism of patients subjected to artificial dialysis is not specifically defined. For example, one selected from γ-linolenic acid, dihomo-γ-linolenic acid and derivatives thereof, or a mixture of two or more of these, or an extract to be obtained from oils and fats such as those of the above-mentioned mold, plants, etc. is mixed with one or more of ordinary, pharmaceutically-acceptable harmless vehicles, carriers, excipients, binders, preservatives, stabilizers, flavorings, etc., and formed into internal preparations such as tablets, granules, capsules, liquid preparations, etc.; suppositories; vaginal preparations; external preparations such as ointments, creams, lotions, etc.; and injections such as sterilized solutions, suspensions, etc. These can be formulated in accordance with the known techniques.
  • For example, one or more of the above-mentioned γ-linolenic acid, etc. may be formulated with a binder such as gelatin, etc., a vehicle such as crystalline cellulose, etc., an excipient such as potato starch, sodium alginate, etc., a sweetener such as lactose, sucrose, etc., into powders, tablets, pills or granules. To prepare capsules, a mixture of γ-linolenic acid, etc. and other oils and fats is encapsulated into soft gelatin capsules, hard gelatin capsules, etc., in accordance with known methods. In addition, cyclodextrin clathrates comprising cyclodextrin and γ-linolenic acid, etc. can also be prepared by known methods. To prepare external preparations, vaseline, paraffin, oils and fats, lanolin, etc. are usable as the base.
  • The above-mentioned γ-linolenic acid, etc. can be combined with ω-3 unsaturated fatty acids such as α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, etc., ω-5 unsaturated fatty acids such as myristoleic acid, etc., ω-7 unsaturated fatty acids such as palmitoleic acid, etc., ω-9 unsaturated fatty acids such as oleic acid, ercylic acid, etc.; and saturated fatty acids such as lauric acid, myristic acid, etc., at any desired proportions. In order to prevent the oxidation of γ-linolenic acid, etc., antioxidants such as vitamin E, ascorbyl palmitate, ascorbyl stearate, etc. may be added thereto.
  • The dose of γ-linolenic acid, dihomo-γ-linolenic acid or its derivative is not specifically defined. However, if too much of it is administered, the patient is apt to have loose bowels. The dose shall be suitably determined, depending on the age, the medical history and the condition of the patient as well as the type of the disorder, etc. To attain the intended effects for the treatment of hyperparathyroidism, the active ingredient may be administrated thereto in an amount of from 50 to 600 mg/day, preferably from 100 to 450 mg/day.
    • BEST MODES FOR CARRYING OUT THE INVENTION
  • Examples of the present invention are described hereinunder.
    • Production Example 1: Capsules
  • 235 parts by weight of oil or fat containing about 22 % by weight of γ-linolenic acid was mixed with 65 parts by weight of vitamin E (TM-70G, produced by Tama Biochemical Co.) by an ordinary method and encapsulated in gelatin capsules (Football-type No. 5, produced by Fuji Capsule Co.) to produce capsules each containing γ-linolenic acid of 50 mg/capsule.
  • The oil or fat containing γ-linolenic acid used herein was extracted according to the method described in Japanese Patent Application Laid-Open No. 63-283589 (1988). Briefly, cultured cells of Mucor circinelloides HUT 1121 (FERM P-9359) was subjected to n-hexane extraction to obtain oil or fat containing γ-linolenic acid.
    • Example: Evaluation of Therapeutic Composition of the Invention
  • The capsules prepared in the above-mentioned Production Example were administered to four patients subjected to artificial dialysis, who suffer from hyperparathyroidism and have the medical history of hemodialytic treatment shown in Table 1 below, at 7 capsules/day (4 capsules after breakfast and 3 capsules after evening meal a day) which corresponds to 350 mg/day in terms of γ-linolenic acid. The administration was started on the same day for the four patients. For the patients Nos. 1 to 3, the administration was continued for 3 months. Then, their data were measured with Allegro Intact PTH kit (produced by Nippon Mediphysics Co.) and are shown in Table 2. For the patient No. 4, the administration was continued for 3 months and thereafter 3 capsules/day (corresponding to 150 mg/day in terms of γ-linolenic acid) were continuously administered thereto after breakfast for further 5 months. Then, its data were measured with a PTH kit "Yamasa" (produced by Yamasa Shoyu Co.) and shown in Table 3. The PTH data of the four patients were periodically measured. Their PTH data before and after the administration are shown below along with the months counted on the basis of the start of the administration. Table 1
    Background of Patients
    Patient No. Sex Age Medical History of Hemodialytic Treatment (at the start of the administration)
    1 Female 44 1 year and 6 months
    2 Female 64 1 year and 2 months
    3 Female 42 10 years and 11 months
    4 Male 46 2 years and 9 months
    Figure imgb0001
    Figure imgb0002
  • From the results in Table 2 and Table 3, it is evident that the PTH values of the four patients who are subjected to artificial dialysis and to whom the therapeutic composition for hyperparathyroidism of the present invention was administered all lowered after the administration. From these, it is obvious that the composition of the present invention is efficacious against hyperparathyroidism. Before and after the administration, any particular medical treatment was not administrated to the patients. There was found no abnormal change in their clinical examination data as periodically measured. The safety of the composition of the present invention was thus confirmed.
    • INDUSTRIAL APPLICABILITY
  • The therapeutic composition of the present invention for hyperparathyroidism of patients who are subjected to artificial dialysis exhibits a sufficient suppressive effect for the hypersecretion of PTH to be caused by hyperparathyroidism and is excellent in safety.

Claims (1)

  1. A therapeutic composition for hyperparathyroidism of patients who are subjected to artificial dialysis, comprising one or more selected from γ-linolenic acid, dihomo-γ-linolenic acid and derivatives thereof.
EP94929663A 1993-12-29 1994-10-14 Therapeutic composition for hyperparathyroidism of patient subjected to artificial dialysis Withdrawn EP0734723A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP355269/93 1993-12-29
JP35526993 1993-12-29
PCT/JP1994/001729 WO1995017889A1 (en) 1993-12-29 1994-10-14 Therapeutic composition for hyperparathyroidism of patient subjected to artificial dialysis

Publications (2)

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EP0734723A1 true EP0734723A1 (en) 1996-10-02
EP0734723A4 EP0734723A4 (en) 2001-04-11

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US5668174A (en) 1997-09-16
WO1995017889A1 (en) 1995-07-06

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